Lung cancer is a major disease with unmet medical need. Identification of molecules that play critical roles in regulating lung malignant pathways is essential for improving the preventive and therapeutic interventions of this fatal disease. The goal of this study is to investigate the roles of PTPN11 (SHP2) in epithelial tumors focusing on lung adenocarcinoma. Mutant EGFR is a major lung adenocarcinoma driver oncogene found in never-smokers. Using novel transgenic mice, we will investigate in Specific Aim 1 whether SHP2 is essential for EGFR mutant-driven lung tumor and study mechanisms by which SHP2 mediates EGFR signaling and lung tumor development. Mutant KRAS is a major lung adenocarcinoma driver oncogene associated with heavy smokers. In Specific Aim 2, we will evaluate the SHP2 dependency of KRAS mutant lung adenocarcinoma and whether SHP2 inhibition prevents cigarette smoke carcinogen-induced lung tumors in transgenic mice. Animal lung and xenograft tumors will be analyzed by quantitative phosphoproteomics to gain insights into the mechanisms of SHP2 dependency of mutant EGFR and KRAS lung carcinoma in vivo. Previous studies of driver oncogenes have been focused on protein tyrosine kinases, while protein tyrosine phosphatases were perceived mostly as tumor suppressors. Consequently, there is near complete lack of knowledge about protein tyrosine phosphatase driver oncogenes in lung adenocarcinoma. PTPN11 mutations occur in lung adenocarcinoma and prostate cancer among other solid tumors. However, it is unclear whether these are passenger mutations or driver oncogene mutations in carcinoma and what properties confer a PTPN11 mutation the oncogenic activity in epithelial cells. In Specific Aim 3, we will analyze oncogenic activities of several PTPN11 mutations in lung epithelial cells to gain insights into the oncogenic activity of PTPN11 mutations in lung cancer. Taken together, this study could reveal important roles of a protein tyrosine phosphatase in two major lung cancer driver oncogene-associated lung adenocarcinoma. It will give novel insights into signaling events critical to both non-smoker and smoker-associated lung adenocarcinoma. In addition to the potential translational significance, by demonstrating the first protein tyrosine phosphatase driver oncogene in epithelial tumors and revealing the SHP2 dependency of KRAS mutant lung adenocarcinoma, the study could have significant conceptual impact in the field. Moreover, the novel Cre recombinase-mediated cassette exchange-enable transgenic mice characterized in this study will give the research community an important resource to accelerate mouse model studies of human diseases.